Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome
Tian Yu,
Linda C Meiners,
Katrin Danielsen,
Monica TY Wong,
Timothy Bowler,
Danny Reinberg,
Peter J Scambler,
Conny MA van Ravenswaaij-Arts,
M Albert Basson
Affiliations
Tian Yu
Department of Craniofacial Development and Stem Cell Biology, King’s College London, London, United Kingdom
Linda C Meiners
Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Katrin Danielsen
Department of Craniofacial Development and Stem Cell Biology, King’s College London, London, United Kingdom
Monica TY Wong
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Timothy Bowler
Department of Internal Medicine, Montefiore Medical Center, New York, United States
Danny Reinberg
Department of Biochemistry and Molecular Pharmacology, Howard Hughes Medical Institute, New York University School of Medicine, New York, United States
Peter J Scambler
Molecular Medicine Unit, University College London Institute of Child Health, London, United Kingdom
Conny MA van Ravenswaaij-Arts
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
M Albert Basson
Department of Craniofacial Development and Stem Cell Biology, King’s College London, London, United Kingdom; MRC Centre for Developmental Neurobiology, King’s College London, London, United Kingdom
Mutations in CHD7 are the major cause of CHARGE syndrome, an autosomal dominant disorder with an estimated prevalence of 1/15,000. We have little understanding of the disruptions in the developmental programme that underpin brain defects associated with this syndrome. Using mouse models, we show that Chd7 haploinsufficiency results in reduced Fgf8 expression in the isthmus organiser (IsO), an embryonic signalling centre that directs early cerebellar development. Consistent with this observation, Chd7 and Fgf8 loss-of-function alleles interact during cerebellar development. CHD7 associates with Otx2 and Gbx2 regulatory elements and altered expression of these homeobox genes implicates CHD7 in the maintenance of cerebellar identity during embryogenesis. Finally, we report cerebellar vermis hypoplasia in 35% of CHARGE syndrome patients with a proven CHD7 mutation. These observations provide key insights into the molecular aetiology of cerebellar defects in CHARGE syndrome and link reduced FGF signalling to cerebellar vermis hypoplasia in a human syndrome.